Mediastinal B-cell Lymphoma Research Articles

Primary mediastinal large B-cell lymphoma is characterized by large-scale copy-neutral loss of heterozygosity.

Development of primary mediastinal B-cell lymphoma (PMBL) is driven by cumulative genomic aberrations. We discovered a unique copy-neutral loss of heterozygosity (CN-LOH) landscape of PMBL which distinguishes this tumor from other B-cell malignancies, including the biologically related diffuse large B-cell lymphoma. Using single nucleotide polymorphism array analysis we identified large-scale CN-LOH lesions in 91% (30/33) of diagnostic PMBLs and both investigated PMBL-derived cell lines. Altogether, the cohort showed 157 extra-large (25.3-248.4Mb) CN-LOH lesions affecting up to 14 chromosomes per case (mean of 4.4) and resulting in a reduction of heterozygosity an average of 9.9% (range 1.3-51%) of the genome. Predominant involvement of terminal chromosomal segments suggests the implication of B-cell specific crossover events in the pathogenesis of PMBL. Notably, CN-LOH stretches non-randomly clustered on 6p (60%), 15 (37.2%), and 17q (40%), and frequently co-occurred with homozygous mutations in the MHC I (6p21), B2M (15q15), and GNA13 (17q23) genes, respectively, as shown by preliminary whole-exome/genome sequencing data. Altogether, our findings implicate CN-LOH as a novel and distinct mutational process contributing to the molecular pathogenesis of PMBL. The aberration acting as "second hit" in the Knudson hypothesis, ranks as the major mechanism converting to homozygosity the PMBL-related driver genes. Screening of the cohort of 199 B cell leukemia/lymphoma whole-genomes revealed significant differences in the CN-LOH landscape of PMBL and other B-cell malignancies, including the biologically related diffuse large B-cell lymphoma.

P1174: THE COMBINATION OF QUALITATIVE AND QUANTITATIVE METABOLIC PARAMETERS PREDICTS PROGRESSION-FREE SURVIVAL IN PATIENTS WITH LARGE B-CELL LYMPHOMAS (LBCL) TREATED WITH ANTI-CD19 CAR-T CELLS.

Background: Autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is an effective therapy for 40% of patients (pts) with relapsed/refractory (R/R) LBCL. Qualitative and quantitative metabolic parameters from the 18-FDG PET-CT scan are tools able to predict outcomes in lymphomas, but their value in the CAR-T setting is still under investigation. Aims: Prognostic role of PET-CT performed before lymphodepletion and 1 month after CAR-T cell infusion, analyzed by qualitative and quantitative parameters Methods: We conducted an observational a prospective study on pts affected by R/R aggressive lymphomas receiving axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel). PET-CT was evaluated before lymphodepletion, at 1 month (M1) and at 3 months (M3) post-infusion using visual assessment with a 5-point Deauville score (DS). Quantitative PET parameters were evaluated with PET-VCAR software (GE Healthcare). The contour of pathological lesions was delineated using semiautomatic contouring systems including a gradient-based algorithm. SUVmax, SUVmean, Metabolic tumor volume (MTV), and Total lesions glycolysis (TLG) were automatically recorded. Total MTV (TMTV) and total TLG (TTLG) were calculated as the sum of all individual lesions. The percentage change in FDG uptake of each parameter between baseline and M1 was defined as Δ=(baseline-M1)/baseline x 100%. Logistic and Cox regression models were applied to evaluate the association between PET parameters at baseline, at M1 and in terms of Δ with respect to clinical response and progression free survival (PFS), respectively. Results: 47 pts were analyzed: median age was 55 years (range, 22-70); histologies included diffuse-large B-cell lymphomas (n=33) and primary mediastinal B-cell lymphomas (n=14); pts received treatment with axi-cel (n=31) or tisa-cel (n=16). Before infusion, 18 (38%) had high LDH, 14 (30%) had extranodal disease and 16 (34%) had bulky disease. Majority of pts [n=41 (84%)] received bridging therapy. At a median follow-up of 12 months (range, 3-29 months), 38 patients are alive and 9 died of disease progression with an estimated 1-year PFS and OS of 46% (95%CI; 30%-60%) and 83% (95%CI; 66%-92%), respectively. Baseline values of SUVmax, but not SUVmean, TTLG, TMTV correlated with poor clinical response [HR 1,49; (95%CI; 1,01-2,2), p=0,04]. By univariate logistic model, a higher ΔSUVmean between baseline and M1 was associated with better response at M3 [odds ratio 3,49, (95%CI; 1,25-9,77), p=0.02]. Univariable Cox analyses showed that a higher ΔSUVmean and ΔTMTV between baseline and M1 were associated with a better PFS [HR 0,63, (95%CI; 0,41-0,96), p=0,03; HR 0,67 (95%CI; 0,48-0,94), p=0,02], respectively. In terms of visual assessment, pts with DS 4-5 at M1 had a significantly higher risk of failure as compared to those with DS 1-3 [HR 2,92, (95%CI; 1,12-7,64), p=0,02]. A combination of M1 DS score and ΔSUV mean showed a better prognosis for patients with DS1-3 (PFS 60%), an intermediate prognosis for those with DS4/5 and high ΔSUVmean (PFS 49%) and a poor prognosis for those with DS4/5 and low ΔSUVmean (PFS 22%), [p=0,009]. In a multivariable analyses, evaluating clinical prognostic factors and PET parameters, a higher risk of failure was observed in pts with high LDH [HR 3,2 (95%CI; 1,30-8,14), p=0,01] whereas a higher ΔSUVmean was associated to a better PFS [HR 0,61 (95%CI, 0,41-0,92), p=0,02]. Summary/Conclusion: Assessment of DS combined with variation of SUVmean at M1 provides informations about early risk of CAR-T failure. A validation group are needed to extend and confirm our observations.

PB2137: INFLUENCE OF PREVIOUS RADIOTHERAPY ON THE EFFECT OF CART CELL THERAPY IN AGGRESSIVE B-CELL LYMPHOMA

Background: In previous studies, radiotherapy has an effect on the number and function of lymphocytes. In recent years, with the advent of CART cell therapy, the PFS and OS of relapsed and refractory highly aggressive B-cell lymphoma have been significantly improved. Whether previous radiotherapy is effective for CART cell therapy The impact is inconclusive. Aims: To investigate the influence of the radiotherapy history before CART cell therapy on the culture, expansion and treatment effect of CART cells in patients with aggressive B-cell lymphoma. Methods: A retrospective study from December 2018 to September 2021 in adult patients with aggressive B-cell lymphoma treated with CART cells at our center who underwent radiotherapy before lymphocyte collection. The patient’s previous radiotherapy dose, radiotherapy distance from lymphocyte collection time, peripheral blood lymphocyte count before lymphocyte collection, CART cell culture dose, reinfusion dose, and curative effect statistics of 3 months after CART cell reinfusion were counted. Statistical methods such as logistic regression and spearman correlation analysis were used for analysis. Results: 16 males and 18 females were eligible, with a median age of 45.5 years (18-86 years). These included 2 Burkitt lymphoma, 26 unspecified diffuse large B-cell lymphoma, 5 primary mediastinal B-cell lymphoma, and 1 primary central lymphoma. The median time from lymphocyte collection to previous radiotherapy was 151 (5-4772) days, and the median radiation dose was 46 (4-66) Gy. The absolute value of lymphocytes before the collection of lymphocytes was 0.79 (0.14-2.58)×10^9/L, which was lower than the normal reference value. The median culture dose of CART cells was 0.837(0.1-7.03)×10^6/kg, and the median infusion dose was 0.837(0.1-4.2)×10^6/kg. After CART cell infusion, the peak CART cell expansion was 18.6(0-919)×10^6/kg, 3-month CR: 20.59%, 3-month ORR: 44.12%. The time interval between previous radiotherapy and lymphocyte collection had a significant effect on 3-month CR, P=0.0417. The effect on 3-month ORR was not statistically significant, P=0.1388. There was no significant effect of previous radiotherapy dose on CR/ORR at 3 months, with P values ​​of 0.9188/0.5078, respectively. The effect of previous radiotherapy dose on the CART cell culture dose and the maximum value of CART cell expansion was not found to be statistically significant. CR and ORR at 3 months after reinfusion were significantly correlated with the reinfusion dose, with P values ​​of 0.0102 & 0.0121, respectively. There was no significant relationship between the absolute value of lymphocytes and the proportion of lymphocytes, the culture dose and the CR/ORR of the curative effect. Summary/Conclusion: Radiotherapy affects the number and cell quality of lymphocytes, the median culture dose is significantly lower than the 2×10^6/kg reported in the literature. In patients with aggressive B-cell lymphoma who had a history of radiotherapy, the CR/ORR at 3 months after CART cell therapy was significantly lower than that reported. This adverse effect was independent of radiation dose. The CR rate is affected by the time interval between radiotherapy and lymphocyte collection. The longer the interval, the greater the adverse effect.

P1180: ARE EXTRANODAL LIMITED-STAGE DIFFUSE LARGE B-CELL LYMPHOMA MORE AGRESSIVE THAN NODAL FORMS?

Background: Limited-stage diffuse large B-cell lymphoma (DLBCL) is associated with favourable outcomes with overall survival of 70-80% at 10 years. Stage-modified IPI (sm-IPI) predicts the risk of relapse and death based on clinical factors that do not include extranodal (EN) involvement, although in some studies it has been associated with worse outcomes. Aims: To analyse the characteristics and outcomes of limited-stage DLBCL in a single center series and evaluate the prognostic impact of EN involvement. Methods: We conducted a retrospective analysis of consecutive patients with newly diagnosed stage I-II DLBCL treated with curative intent at a single centre from 2015 to 2019. Primary central nervous system (CNS) lymphoma, primary testicular lymphoma, primary mediastinal B-cell lymphoma and transformed lymphoma were excluded. Response to therapy was assessed according to Lugano criteria. Overall (OS) and progression free survival (PFS) were calculated by Kaplan-Meier method and comparisons done by the log rank test. Cumulative incidence of relapse was calculated using competing risk models and Gray test for group comparisons. Cox regression was used to identify prognostic factors for PFS. Results: Of 152 patients identified, 53 (35%) had EN disease and 99 (65%) were nodal (N). The most common EN sites were stomach (30%), sinus/nasal cavity (13%), skin and soft tissue (9%) and breast (9%). Seventy-two (47%) had low risk sm-IPI (45 N; 27 EN). Clinical characteristics were similar between both groups, except for stage (stage I in 50.9% of EN vs 32.3% of N cases) and bulky disease (EN 15.1% vs N 37.4%). All patients received R-CHOP (median 6 cycles; range 1-8). Eight patients, all with EN involvement (3 sinus/nasal cavity, 2 breast, 2 bone and 1 orbit), received CNS prophylaxis. Seventeen out of 152 patients received additional radiotherapy (RT), 71% of whom had nodal involvement; 16/17 were irradiated due to bulky disease and/or treatment with abbreviated immunochemotherapy. Globally, 89% patients had a complete response (CR) to treatment: 85% in the N and 96% in the EN group (p=0.212). Nine patients relapsed at a median of 18 (7-52) months after obtaining CR (6 from the N and 3 from the EN group). The 4-year cumulative incidence of relapse was similar: 11.2% (95%CI 9.0-13.9%) in EN and 6.7% (95%CI 5.9-7.5%) in N group (p=0.778). No gastric lymphomas relapsed. The most common sites of relapse were lymph nodes (3), soft tissue (3) and CNS (2). Nineteen (14 N; 5 EN) patients died at a median of 12 (0-47) months after starting treatment, mostly (52.6%) due to lymphoma progression. With a median follow-up of 43 months, 4-year OS and PFS were 87% and 82%, respectively. No significant survival differences were observed in patients with N or EN presentation with a 4-year PFS of 81.8% and 81.3% (p=0.428), respectively. On multivariable analysis adjusting for RT, sm-IPI and bulky disease, EN involvement was not associated with a decreased PFS compared with N involvement (HR 0.77; 95%CI 0.31-1.90; p=0.570). Image:Summary/Conclusion: Our study corroborates the very favourable outcomes of localized DLBCL. We could not find differences in PFS according to N and EN presentations when controlling for other prognostic factors. These results do not support different treatment strategies for EN disease; however, due to limited sample size the role of RT and the prognostic impact of specific locations cannot be fully ascertained.

High efficacy of intensive immunochemotherapy for primary mediastinal B-cell lymphoma with prolonged follow up

Primary mediastinal B-cell lymphoma (PMBL) is currently curable in 85–95% of patients. Treatment regimens frequently used include RCHOP ± radiotherapy, DAEPOCH-R, or occasionally more intensive protocols. Here we present results of treatment of 124 patients with PMBL over a period between 2004 and 2017 with the use of a protocol designed for aggressive B-cell lymphoma GMALL/B-ALL/NHL2002 including 6 cycles of alternating immunochemotherapy with intermediate-dose methotrexate in each cycle, and reduced total doxorubicin dose (100 mg/m2 for whole treatment). Majority of patients (77%) received consolidative radiotherapy. A median (range) age of patients was 30 (18–59) years, and 60% were female. With a median (range) follow up of 9 (1–17) years, 5-year overall survival (OS) and 5-year progression free survival (PFS) were 94% and 92%, respectively. Positron emission tomography—computed tomography (PET-CT) results at the end of chemotherapy were predictive for outcome: OS and PFS at 5 year were 96% and 94% in PET-CT negative patients, respectively, and 70% and 70% in PET-CT-positive patients (p = 0.004 for OS, p = 0.01 for PFS). Eight (6%) patients had recurrent/refractory disease, however, no central nervous system (CNS) relapse was observed. Acute toxicity included pancytopenia grade 3/4, neutropenic fever, and treatment related mortality rate of 0.8%. Second malignancies and late cardiotoxicity occurred in 2.4% and 2.4% of patients, respectively. Intensive alternating immunochemotherapy protocol GMALL/B-ALL/NHL2002 is curative for more than 90% of PMBL patients and late toxicity in young patients is moderated. The attenuated dose of doxorubicin and intermediate dose of methotrexate may contribute to low incidence of late cardiotoxicity and effective CNS prophylaxis.

Less Intensive Regimens May Still Be Suitable for the Initial Treatment of Primary Mediastinal B-Cell Lymphoma in Resource-Limited Settings.

Primary mediastinal B-cell lymphoma (PMBCL) is an uncommon disease, consisting of 2–4% of non-Hodgkin lymphomas. Radiotherapy-free DA-EPOCH-R and R-CHOP plus radiotherapy (RT) have been the upfront standard regimens worldwide. However, performing DA-EPOCH-R in resource-constrained settings can be burdensome, especially in low/middle-income countries, where data on PMBCL are still largely unknown. We retrospectively analyzed 93 patients with PMBCL diagnosed between 2008 and 2018 with the intention of comparing the characteristics of the patients and the results obtained with each protocol and to verify if the use of less intensive chemotherapy is still possible to be used. The median age was 28 years, 59.1% were female, 42.3% were in advanced stages, and 92.1% were with bulky disease. DA-EPOCH-R (41.9%), R-CHOP (35.5%), and R-CHOEP (22.6%) were the regimens used, and no difference was observed in the characteristics of the patients. After four cycles of chemotherapy, complete response (CR), partial response (PR), and progressive disease (PD) rates were 40%, 55.7%, and 4.5%, respectively. At the end of treatment, metabolic CR and PD rates were 56.8% and 11.1%. RT was performed in 42.1% of DA-EPOCH-R, 75% of R-CHOP, and 83% of R-CHOEP, and switched PR to CR in 73.7%. Estimated 5-year PFS and OS were 77.2% and 77.4%, respectively. Only LDH levels remained independently associated with PFS, and type of treatment was not associated with OS, PFS, or relapse rate. Therefore, we conclude that in a resource-constrained setting, R-CHOP or R-CHOEP could be still safely adopted in upfront treatment for PMBCL.

KEYNOTE B68: Open-label phase 2 study of the efficacy and safety of pembrolizumab administered every six weeks in patients with relapsed or refractory classical Hodgkin lymphoma or primary mediastinal B-cell lymphoma.

TPS7585 Background: Classical Hodgkin lymphoma (cHL) and primary mediastinal B-cell lymphoma (PMBCL) frequently harbor amplifications at 9p24.1, leading to overexpression of PD-L1 and PD-L2, suggesting a genetically driven vulnerability to programmed death 1 (PD-1) blockade. The PD-1 inhibitor pembrolizumab, dosed at 200 mg every 3 weeks (Q3W), demonstrated strong antitumor activity and acceptable safety that led to approvals for adult and pediatric patients with relapsed or refractory (R/R) cHL and R/R PMBCL. Efficacy, safety, and pharmacokinetic (PK) results from studies in solid tumors have since led to accelerated approval for the pembrolizumab 400 mg Q6W regimen for all indications in adults; however, further efficacy and safety data are needed for hematologic indications. The open-label, single-arm, multisite, global, phase 2 KEYNOTE-B68 study (NCT04875195) evaluates the safety, efficacy, and PK profile of pembrolizumab 400 mg Q6W in patients with R/R cHL or PMBCL. Methods: Patients must have histologically confirmed R/R cHL (cohort 1) or R/R PMBCL (cohort 2) per WHO classification and radiographically measurable disease per the Lugano 2014 classification criteria and must not have previously received treatment with anti–PD-1 therapy. Eligible patients must have failed to respond to or relapsed after receiving an autologous stem cell transplant (ASCT) or must be ineligible for ASCT and must have failed to respond or relapsed after ≥1 (cHL) or ≥2 (PMBCL) prior lines of therapy; patients with PMBCL must have received ≥1 line of therapy containing rituximab. Approximately 60 patients will be enrolled. They will receive pembrolizumab 400 mg IV Q6W for up to 18 cycles. Disease assessments will occur Q12W by investigator per the Lugano 2014 response criteria. Local radiographic assessments will be collected by computed tomography Q12W and by positron emission tomography at weeks 12 and 24 and to confirm complete response. Adverse events will be monitored and assessed by investigators throughout the study, and their severity will be graded per NCI Common Terminology Criteria for Adverse Events, version 5.0 guidelines. Patients who receive an allogeneic SCT within 2 years of the last dose of study treatment will be monitored for 18 months after SCT for events of clinical interest. The primary end point (assessed per cohort) is objective response rate by investigator per the Lugano 2014 classification criteria. Secondary end points (assessed per cohort) include duration of response by investigator assessment, characterization of the PK profile and immunogenicity for pembrolizumab 400 mg Q6W, and safety. Exploratory end points assessed per cohort include overall survival, progression-free survival per the Lugano 2014 criteria, and molecular biomarker analyses. Clinical trial information: NCT04875195.

PJP pneumonia in brentuximab vedotin recipients.

e19533 Background: Pneumocystis pneumonia (PJP) is a catastrophic infection seen in the context of low CD4 counts. Brentuximab vedotin (BV) is a drug antibody conjugate targeting CD30 and is used to treat patients with Hodgkin’s lymphoma (HL) and T-cell lymphoma (TCL). PJP prophylaxis is not currently recommended for patients receiving BV-based treatment despite co-expression of CD30 on CD4 cells. The frequency of PJP following BV remains poorly defined. Methods: We evaluated patients who received BV between January 1, 2011 and October 31, 2021 at Mayo Clinic for the development of PJP. Patient demographics and clinical characteristics including underlying disease, chemotherapy regimen, absolute lymphocyte count (ALC), and steroid exposure were collected. Patients who developed PJP more than 3 months after their last BV exposure were excluded. Results: Of 402 BV recipients identified, 63 received PJP prophylaxis and were omitted. Fourteen of the 339 (4.1%) not on prophylaxis developed PJP following BV. Those infected had a median age of 61 (22-87), 71% were male. The most common diagnoses were HL, TCL, and primary mediastinal B-cell lymphoma at rates of 57%, 21%, and 14% respectively. Therapy regimens included BV monotherapy, BV-CHP, and BV-AVD at rates of 43%, 21%, and 14% respectively. BV represented median 2nd line of therapy (1-10) and patients received median of 3 doses (1-10) prior to PJP diagnosis. Patients with PJP had median ALC of 620 (370-3500). 71.4% (10/14) had an ALC less than 750 and among those with ALC greater than 1000, 75% (3/4) had underlying diagnosis of HL. Three patients had CD4 count measured at time of PJP diagnosis with median value of 157 (5-175). 57.1% (8/14) had no steroid exposure beyond the treatment regimen. 14.3% (2/14) were on chronic doses of 5mg prednisone for autoimmune conditions. Short bursts of steroids (prednisone 40 mg) prior to PJP were seen in 21.4% (3/14) with median exposure of 8 days (7-10). One patient had prolonged steroid exposure but was weaned off 17 days prior to PJP diagnosis. 71.4% were older than 50 years at time of PJP. Conclusions: We observed rates of PJP above the commonly accepted threshold of 3.5% for recommending prophylaxis. Among patients with an ALC greater than 1000, 75% had HL raising the question of a qualitative defect in immunity. Close ALC monitoring is recommended for patients receiving BV with a low threshold to institute PJP prophylaxis, especially amongst those older than 50 or with a diagnosis of HL.[Table: see text]

Does ethnicity matter? A two-statewide population based analysis of outcomes of primary mediastinal B-cell lymphoma in Hispanics.

e19568 Background: Primary mediastinal B-cell lymphoma (PMBCL) is considered a rare distinct clinicopathological and molecular subtype of diffuse large B-cell lymphoma (DLBCL), mainly affecting females in their 4th and 5th decades [1,2,3]. Since the 1960s, there has been a significant increase in the number of immigrants to the US; and the states of Florida (FL) and Texas (TX) are well known for their Hispanic (HI) enriched population. Since there is scarce data of PMBCL in HI; we researched demographics, treatment patterns and outcomes in H compared to Non-Hispanics (NH) from FL and TX. Methods: This is a retrospective study of patients diagnosed with PMBCL from the Texas Cancer Registry (TCR) and the Florida Cancer Data System (FCDS), with years of analysis 2006-2017. Patients were identified by the International Classification of Diseases for Oncology Third Edition (ICD-O-3). Key variables collected included gender, race, ethnicity, dates at diagnosis and death, primary payer at diagnosis, stage, type of treatment, poverty index, and vitality status. The significance of variation in the distribution of categorical outcomes with ethnicity (H, NH) was assessed with Fisher’s Exact tests or Pearson’s Chi-square tests as appropriate. Survival distributions were described with Kaplan-Meier curves, and the significance of variation in median survival with ethnicity was assessed with log-rank testing. All statistical testing was two-sided with a significance level of 5%. Results: We had 2 cohorts; cohort A (A) includes 19 H vs. 89 NH from TX, cohort B (B), 27 H vs. 121 NH from FL. The median age at diagnosis in A was 33 years (y) in H vs 40 y in NH ( p-value = 0.091); while median age in B was 36 y in H vs 46 y in NH ( p-value = 0.005). Regarding poverty index; in A, most of H were in the 10-20% bracket, and most NH were in the 5-10% bracket. On the contrary, in B, most of H were in the 5-10%, and most NH were in the 10-20% bracket. Lack of insurance was more prevalent in H in A vs. NH, 42% vs. 12%, respectively, where it was less prevalent in H vs. NH in B, 8% vs. 5%. Multiple agents of chemotherapy were delivered to 74% of H, 70% of NH vs. 82% of H and 65% of NH with p-value = 0.292 and 0.635 in A and B, respectively. In A, the NH had better median survival (m) than H, not reached vs. 10.3 y, respectively. In B, H had better m than the NH, 10.7 y vs. not reached, respectively. The 5 y survival probability in A was even among H and NH; 0.702 [95% CI 0.49-1] and 0.732 [95% CI 0.578 - 0.9280], respectively. While 5 y survival probability in B was higher in H compared to NH, 0.923 [95% CI 0.675 -0.869] and 0.766 [95% CI 0.434 - 0.615], respectively. The overall survival (OS) difference in A and B, H vs. NH was not statistically significant. Conclusions: Despite some identified demographic differences in patients diagnosed with PMBCL, comparing H vs. NH on each cohort, there was no statistically significant difference in the overall survival probability.

STR Profiling Reveals Tumor Genome Instability in Primary Mediastinal B-Cell Lymphoma.

Primary mediastinal B-cell lymphoma (PMBCL) is the only non-Hodgkin’s lymphoma variant responding to immune checkpoint inhibitor (ICI) therapy, approximately in half of the cases; however, no molecular markers predicting a response to ICI therapy in PMBCL have been described so far. In this study, we assessed the incidence of the loss of heterozygosity (LOH), elevated microsatellite alteration at selected tetranucleotides (EMAST), and microsatellite instability (MSI) in the tumor genomes of 72 patients with PMBCL undergoing high-dose chemotherapy treatment at the National Research Center for Hematology (Moscow, Russia). Tumor DNA was isolated from biopsy samples taken at diagnosis. Control DNA was isolated from the blood of patients in complete remission or from buccal epithelium. STR-profiles for LOH and EMAST were assessed by PCR with COrDIS Plus multiplex kit (Gordiz Ltd., Moscow, Russia). LOH was detected in 37 of 72 patients (51.4%). EMAST was found in 40 patients (55.5%); 24 had a combination of EMAST with LOH. MSI-high was not found, while MSI-low was detected only in one patient. The association of certain genetic lesions with the clinical outcome in patients receiving treatment according to the standard clinical protocol R-Da-EPOCH-21 has been estimated (58 patients out of 72) and no associations with the worst overall or event-free survival were found.

SP-0026 Role of radiotherapy and dose-densification of in primary mediastinal B-cell lymphoma

SP-0026 Role of radiotherapy and dose-densification of in primary mediastinal B-cell lymphoma

Noninvasive Prenatal Test Results Indicative of Maternal Malignancies: A Nationwide Genetic and Clinical Follow-Up Study.

Noninvasive prenatal testing (NIPT) for fetal aneuploidy screening using cell-free DNA derived from maternal plasma can incidentally raise suspicion for cancer. Diagnostic routing after malignancy suspicious-NIPT faces many challenges. Here, we detail malignancy suspicious-NIPT cases, and describe the clinical characteristics, chromosomal aberrations, and diagnostic routing of the patients with a confirmed malignancy. Clinical lessons can be learned from our experience. Patients with NIPT results indicative of a malignancy referred for tumor screening between April 2017 and April 2020 were retrospectively included from a Dutch nationwide NIPT implementation study, TRIDENT-2. NIPT profiles from patients with confirmed malignancies were reviewed, and the pattern of chromosomal aberrations related to tumor type was analyzed. We evaluated the diagnostic contribution of clinical and genetic examinations. Malignancy suspicious-NIPT results were reported in 0.03% after genome-wide NIPT, and malignancies confirmed in 16 patients (16/48, 33.3%). Multiple chromosomal aberrations were seen in 23 of 48 patients with genome-wide NIPT, and a malignancy was confirmed in 16 patients (16/23, 69.6%). After targeted NIPT, 0.005% malignancy suspicious-NIPT results were reported, in 2/3 patients a malignancy was confirmed. Different tumor types and stages were diagnosed, predominantly hematologic malignancies (12/18). NIPT data showed recurrent gains and losses in primary mediastinal B-cell lymphomas and classic Hodgkin lymphomas. Magnetic resonance imaging and computed tomography were most informative in diagnosing the malignancy. In 231,896 pregnant women, a low percentage (0.02%) of NIPT results were assessed as indicative of a maternal malignancy. However, when multiple chromosomal aberrations were found, the risk of a confirmed malignancy was considerably high. Referral for extensive oncologic examination is recommended, and may be guided by tumor-specific hallmarks in the NIPT profile.

Circulating tumor DNA in primary mediastinal large B-cell lymphoma versus classical Hodgkin lymphoma: a retrospective study

Few data exist concerning circulating tumor DNA (ctDNA) relevance in primary mediastinal B-cell lymphoma (PMBL). To explore this topic, we applied a 9-gene next-generation sequencing pipeline to samples from forty-four PMBL patients (median age 36.5 years). The primary endpoint was a similarity between paired biopsy/plasma mutational profiles. We detected at least one variant in 32 plasma samples (80%). The similarity between the biopsy and ctDNA genetic profiles for the 30 patients with paired mutated biopsy/plasma samples was greater than or equal to 80% in 19 patients (63.3%). We then compared PMBL ctDNA features with those of a cohort of Hodgkin lymphoma patients (n = 60). The top three mutated genes were SOCS1, TNFAIP3, and B2M in both lymphoma types. PMBL displayed more alterations in TNFAIP3 (71.9% vs. 46.3%, p = 0.029) and GNA13 (46.9% vs. 17.1%, p = 0.013) than cHL. Our 9-gene set may delineate tumor genotypes using ctDNA samples from both lymphoma types.

Chylotamponade in Pediatric Primary Mediastinal Large B-Cell Lymphoma.

Chylotamponade involves rapid accumulation of chyle in the pericardium elevating the pericardial pressures above normal right heart filling pressures, and is extremely rare. A 12-y-old boy presented to the emergency with complaints of facial puffiness for 1 mo and breathing difficulty for 1 wk. The neck veins were distended, and the heart sounds were muffled. A chest CT demonstrated a large anterior mediastinal mass withpleural and pericardial effusions. Echocardiography confirmed cardiac tamponade. Pericardiocentesis revealed chylopericardium. He was placed on a chyle leak diet, and the drain was removed after 48 h. Biopsy of the mediastinal mass revealed a primary mediastinal B-cell lymphoma. He was successfully managed with chemotherapy. The index case demonstrates how prompt identification and management of chylotamponade and treatment of the underlying cause can lead to good clinical outcomes.

The prospective on molecular diagnostics of primary mediastinal B-cell lymphoma and its clinical implications

原发性纵隔大B细胞淋巴瘤（PMBL）是一类少见的侵袭性大B细胞淋巴瘤，具有典型的临床病理学特征。本文总结PMBL的临床、形态和免疫表型特征；阐述PMBL分子基因研究的新发现；讨论PMBL的主要鉴别诊断。对PMBL发病分子机制的研究进展不仅显著提高了诊断准确性，而且也为研发难治/复发性疾病的新型药指明了方向。.

Grey zone lymphoma - diagnostic and therapeutic challenge

Introduction. ?Grey zone Lymphoma?? is associated with various entities. The last published classification of lymphoproliferative neoplasms includes mediastinal grey zone lymphoma. Precise diagnostic criteria are insufficient and establishing a diagnosis is as complex as deciding on treatment options. In this article pathologist and hematologist discuss issues on this topic through case presentation and literature review. Clinical characteristics. It presents in the younger population usually with a mediastinal mass, sometimes large, with compressive symptoms. Pathologic characteristics. Some cases can?t be classified neither as Hodgkin nor Primary mediastinal B-cell lymphoma. Morphology resembles Hodgkin, but with a positive immunophenotype for primary mediastinal or diffuse large B-cell lymphoma, and vice versa. Case report. We presented a case of a 33-year-old male with cervical lymphadenomegaly, B symptoms and clinical deterioration during the diagnostic period. After the first biopsy, differential diagnosis was Epstein-Barr virus-associated lymphoproliferative disorder or classical Hodgkin lymphoma. The second biopsy confirms Epstein-Barr virus-positive diffuse large B-cell lymphoma. The World Health Organization Classification of lymphoproliferative neoplasms - clinical perspective. The term ?grey zone lymphoma? is associated with overlapping diagnosis or uncertainty in diagnosis in more clinical settings than the ones provided in the 5th World Health Organization Classification. Discussion. For now, chemotherapeutic regimen (rituximab-cyclophos phamide, doxorubicin, vincristine, prednisone) stays the standard first line therapy for diffuse large B-cell lymphoma regardless of the Epstein- Barr virus status. Mediastinal grey zone lymphoma treatment varies: chemotherapeutic regimen (rituximab-cyclophos phamide, doxorubicin, vincristine, prednisone) was linked with better outcomes than chemotherapeutic regimen (adriablastin, bleomycin, vinblastine, dacarbazine) +/-R, but for some patients chemotherapeutic regimen (dose adjusted-etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) might be beneficial. Conclusion. Grey zone lymphoma is a rare hematologic malignancy that needs extensive sampling for correct diagnosis and is still subject to inter-observer variability.

Prognostic significance of clinical characteristics and 18Fluorodeoxyglucose-positron emission tomography/computed tomography quantitative parameters in patients with primary mediastinal B-cell lymphoma.

ObjectivePrimary mediastinal B-cell lymphoma (PMBCL) lacks standard treatment regimens. This study aimed to identify the disease’s clinical features and prognostic factors.MethodsThis retrospective study included 56 patients with PMBCL. Patient demographic details and clinicopathological characteristics were summarized, and their effects on progression-free survival (PFS) and overall survival (OS) were analyzed.ResultsThe median patient age was 29 years (range, 14–56). Twenty-two patients received DA-EPOCH-R (dose-adjusted etoposide, vincristine, and doxorubicin for 96 hours with bolus doses of cyclophosphamide and oral prednisone, as well as rituximab), and 34 patients received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). Clinical/laboratory parameters, overall response rates, and 5-year PFS and OS rates did not differ between the treatment groups. Kaplan–Meier analysis indicated that late-stage disease and a higher International Prognostic Index (IPI) were associated with shorter PFS and OS. Furthermore, patients with B symptoms and first-line treatment non-responders exhibited worse OS. 18Fluorodeoxyglucose-positron emission tomography/computed tomography quantitative parameters, such as higher metabolic tumor volume (MTV) and total lesion glycolysis (TLG), were corrected with shorter PFS.ConclusionsThis study revealed that stage IV disease, higher IPI, and B symptoms were poor prognostic factors in patients with PMBCL. Significantly, higher MTV and TLG portended worse PFS.

Dose-adjusted EPOCH-R is not superior to sequential R-CHOP/R-ICE as a frontline treatment for newly diagnosed primary mediastinal B-cell lymphoma: Results of a bi-center retrospective study.

PurposePrimary mediastinal B‐cell lymphoma (PMBCL) is a rare subtype of diffuse large B‐cell lymphoma (DLBCL). Despite its aggressive course, PMBCL is considered curable. While in recent years dose‐adjusted (DA) EPOCH‐R (rituximab, etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin) has become widely endorsed as first‐line therapy for newly‐diagnosed PMBCL, the optimal treatment for this disease and the role of radiotherapy (RT) remains unclear. DA‐EPOCH‐R provides good clinical outcomes, albeit is associated with short‐ and long‐term toxicity. To address this issue, the current retrospective bi‐icenter analysis compared efficacy and toxicity of DA‐EPOCH‐R and a less toxic R‐CHOP/R‐ICE regimen used for the treatment of newly‐diagnosed PMBCL.Patients and MethodsThe study included all patients with a histologically confirmed PMBCL diagnosis treated with DA‐EPOCH‐R or R‐CHOP/R‐ICE between 01/2013‐12/2020 at two tertiary medical centers. Patient demographic and clinical data were derived from institutional electronic medical records. The analysis included 56 patients: 31 received DA‐EPOCH‐R and 25 – R‐CHOP/R‐ICE.ResultsAt a median follow‐up of 1.9 years (IQR 3.1 years), similar progression‐free survival (2.1 versus 2.4 years; p = 0.7667), overall survival (2.5 versus 2.7 years; p = 0.8047) and complete response (80%) were observed in both groups. However, DA‐EPOCH‐R was associated with significantly longer hospitalization required for its administration (p < 0.001) and a trend for higher frequency of infections, stomatitis, thrombotic complications and febrile neutropenia‐related hospitalizations.ConclusionDA‐EPOCH‐R and R‐CHOP/R‐ICE provide similarly encouraging outcomes in newly‐diagnosed PMBCL patients. R‐CHOP/R‐ICE is associated with lower toxicity and significantly reduced hospitalization. Our findings suggest that this regimen may be considered as an alternative to DA‐EPOCH‐R in this patient population.

Safety and Efficacy of Vibostolimab and Pembrolizumab in Patients with Relapsed or Refractory Hematologic Malignancies: A Multicohort, Open-Label, Phase 2 Study

Background: The T-cell immunoglobulin and ITIM domain (TIGIT) is highly coexpressed with programmed cell death 1 (PD-1) on both CD4 and CD8 T cells in cancers. Blockade of TIGIT with vibostolimab (MK-7684) has demonstrated antitumor activity in multiple preclinical tumor models. Inhibition of the PD-1 pathway with pembrolizumab has demonstrated efficacy and safety in several hematologic malignancies. Enhanced antitumor activity with anti-TIGIT and anti-PD-L1 combination therapy has been seen in a preclinical model. A multicohort, open-label, phase 2 study will evaluate the safety and efficacy of MK-7684A, a coformulation of vibostolimab and pembrolizumab, in patients with relapsed or refractory (r/r) hematologic malignancies.Study Design and Methods: This two-part phase 2 study includes a signal-finding phase (part 1) with the option for a dose-expansion phase (part 2), depending on the observed risk-benefit profile from part 1. Patients must have confirmed diagnosis of r/r disease, including classical Hodgkin lymphoma (cHL; cohort A or B), primary mediastinal B-cell lymphoma (PMBCL; cohort A or B), follicular lymphoma (FL; cohort C), diffuse large B-cell lymphoma (DLBCL; cohort D), multiple myeloma (MM; cohort E), or non-Hodgkin lymphoma (NHL; cohort F) (Table 1). Three hundred thirty participants are expected to enroll in part 1 (signal finding) and part 2 (cohort expansion). In part 1, patients in cohorts A-F will receive MK-7684A (vibostolimab 200 mg + pembrolizumab 200 mg) by IV infusion every 3 weeks (Q3W) for up to 35 cycles. Patients will continue treatment until investigator-determined PD, start of new anticancer treatment, documented complete response, or completion of maximum 35 cycles of treatment. Safety data from the first 12 treated patients from any cohort will be collected. Dose-limiting toxicities (DLTs) will be monitored for the first 6 weeks of continuous treatment. If ≥5 of the 12 patients experience DLTs during this period, enrollment may be discontinued. After the DLT review period, safety data will be collected every 6 months for all enrolled patients. Efficacy assessments will be performed Q3W, with the initial tumor imaging performed ≤28 days after enrollment and repeated at 12 weeks (cohorts A-D, F) or 4 weeks (cohort E) after enrollment. Adverse events (AEs) will be monitored throughout the study, and severity will be graded according to the guidelines outlined in NCI CTCAE version 5.0. Each patient will be monitored for AEs and serious AEs for 30 day and 90 days, respectively, after discontinuation of study intervention. The primary end point for part 1 is the number and proportion of patients with DLTs, AEs, and discontinuations from study treatment due to AEs. Safety and tolerability will be assessed by clinical review. Secondary end points include investigator-assessed objective response rate, investigator-assessed duration of response, disease control rate, and pharmacokinetic end points. Overall survival, progress-free survival, health-related quality of life assessments, and molecular assessments will be exploratory. In the part 2 dose-expansion phase, the plan is to enroll approximately 120 patients from cohorts B-E to receive up to 35 cycles of MK-7684A Q3W; 30 additional patients may be enrolled in a cohort expansion (cohort G) to receive vibostolimab monotherapy Q3W for up to 35 cycles. Cohort G will include patients with cHL or PMBCL with PD after ≥2 or ≥3 prior therapies, FL after ≥2 prior therapies, DLBCL after ≥2 prior therapies, and/or MM after ≥3 prior therapies. [Display omitted] DisclosuresYusuf: Merck & Co., Inc.: Current Employment. Jemielita: Merck & Co., Inc.: Current Employment, Other: Current Stockholder. Marinello: Merck & Co., Inc.: Current Employment, Other: Current Stockholder.

Predictors of Relapse and Survival Following Autologous Stem Cell Transplant in Patients with Diffuse Large B-Cell Lymphoma

Background: Although the majority of patients with diffuse large B-cell lymphoma (DLBCL) can be cured with intensive chemotherapy and rituximab, 30-40% of patients will be refractory to or relapse after first line treatment. For these patients, the current standard of care is salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT). Prior studies have largely examined clinical risk factors associated with higher risk of relapse after ASCT; however, there is limited data integrating both pathologic and molecular features. Thus, we aimed to identify high-risk features associated with relapse and survival after ASCT using a combination of clinical, molecular, pathologic, and transplant characteristics.Methods: We retrospectively analyzed the medical records of all adult patients with DLBCL who underwent ASCT at our two institutions from 2010 to 2020. Patients with primary CNS lymphoma, primary mediastinal B-cell lymphoma, or Burkitt lymphoma were excluded. We analyzed demographics, clinical characteristics, cell of origin (COO) by immunohistochemistry (IHC), fluorescence in-situ hybridization (FISH) testing, and treatment/transplant characteristics. The primary endpoints were 3-year progression-free survival (PFS) and overall survival (OS) from ASCT. The Kaplan-Meier method was used to estimate survival with univariate and multivariate Cox proportional hazards regression performed to identify factors associating with PFS and OS, summarized using hazard ratios (HR) with 95% confidence intervals (CI).Results: A total of 235 DLBCL patients underwent ASCT from 2010 to 2020. Median age at ASCT was 61 years (range: 25-75) and 63% were male. At DLBCL diagnosis, 80% had advanced stage disease, 74% had extranodal involvement, 13% had poor performance status, and 65% had elevated lactate dehydrogenase (LDH). 71 patients (30%) had a prior or concurrent indolent lymphoma diagnosis indicating transformed disease. Of the patients with available COO and molecular data, 115 (60%) had germinal center B-cell (GCB) phenotype by IHC, 10 (6%) had a single MYC rearrangement by FISH, and 35 (22%) had MYC plus BCL2 and/or BCL6 rearrangements (DHL/THL). After first-line treatment, 12% remained refractory and 62% later relapsed at a median of 13 months (range: 1-240). Patients received a median of 2 (range: 1-5) lines of treatment pre-ASCT. At time of ASCT, 66% were in complete response (CR) and 32% were in partial response (PR) by standard of care imaging and response criteria.With median follow-up of 5.2 years from time of ASCT, 98 patients (42%) relapsed and 78 (33%) died. 3-year PFS and OS were 58% (95% CI 51-64%) and 74% (95% CI 67-79%), respectively. In univariate analysis, factors associated with worse PFS and worse OS included 3 or more lines of treatment pre-ASCT (p<0.01 for both) and non-CR at ASCT (p<0.01 for both) (Figure 1A and B). Transformed disease was also associated with worse PFS (p=0.03). In multivariate analysis, non-CR at ASCT remained significant (HR 2.22, 95% 1.26-3.90, p<0.01) for worse OS, along with non-GCB COO (HR 1.81, 95% CI 1.03-3.18, p=0.04) and age >60 at ASCT (HR 1.92, 95% CI 1.06-3.47, p=0.03) (Figure 1C). Stratifying by COO and disease status at transplant, 3-year OS was best in the GCB/CR group (84%, 95% CI 73-90%), while worse but similar in the GCB/non-CR and non-GCB/CR groups (68%, 95% CI 51-80% and 71%, 95% CI 56-83%, respectively) (Figure 1D). The non-GCB/non-CR group had the worst 3-year OS (48%, 95% CI 27-67%). No individual factors beyond CR/non-CR at ASCT were associated with worse 3-year PFS. Notably, DHL/THL patients (77% of whom were in CR at time of ASCT) had similar PFS (p=0.08) and OS (p=0.30) to non-DHL/THL patients, suggesting that response to therapy may be more prognostic than high-risk molecular features alone.Conclusions: This analysis indicated that factors associated with OS after ASCT were disease status at time of transplant and COO, with non-GCB patients not in CR having the poorest outcomes. GCB patients not in CR were still able to be cured by ASCT at a high rate. Molecular rearrangements including DHL/THL were not prognostic, although interpretation may be limited by the modest number of DHL/THL patients. These findings may inform which patients should undergo ASCT, while the highest risk group may be better treated with alternatives including novel targeted agents or chimeric antigen receptor cell therapy. [Display omitted] DisclosuresBachanova: FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; KaryoPharma: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fehniger: Compass Therapeutics: Research Funding; Affimed: Research Funding; ImmunityBio: Research Funding; Wugen: Consultancy, Current equity holder in publicly-traded company, Patents & Royalties: related to memory like NK cells, Research Funding; OrcaBio: Other; Kiadis: Other; HCW Biologics: Research Funding; Indapta: Other. Weisdorf: Fate Therapeutics: Research Funding; Incyte: Research Funding.